Elsevier

The Lancet

Volume 379, Issue 9813, 28 January–3 February 2012, Pages 373-383
The Lancet

Seminar
Thalassaemia

https://doi.org/10.1016/S0140-6736(11)60283-3Get rights and content

Summary

Thalassaemia is one of the most common genetic diseases worldwide, with at least 60 000 severely affected individuals born every year. Individuals originating from tropical and subtropical regions are most at risk. Disorders of haemoglobin synthesis (thalassaemia) and structure (eg, sickle-cell disease) were among the first molecular diseases to be identified, and have been investigated and characterised in detail over the past 40 years. Nevertheless, treatment of thalassaemia is still largely dependent on supportive care with blood transfusion and iron chelation. Since 1978, scientists and clinicians in this specialty have met regularly in an international effort to improve the management of thalassaemia, with the aim of increasing the expression of unaffected fetal genes to improve the deficiency in adult β-globin synthesis. In this Seminar we discuss important advances in the understanding of the molecular and cellular basis of normal and abnormal expression of globin genes. We will summarise new approaches to the development of tailored pharmacological agents to alter regulation of globin genes, the first trial of gene therapy for thalassaemia, and future prospects of cell therapy.

Introduction

Abnormalities in the structure and synthesis of the α-like and β-like globin chains that form tetramers of haemoglobin (α2β2) lead to the most common forms of inherited anaemias.1 In thalassaemia, there are defects in the production of either the α-like (α-thalassaemia2) or the β-like (β-thalassaemia3) globin chains. From the 1970s, these diseases, which specifically affect red blood cells, were among the first to be analysed with the use of molecular biology. Their detailed characterisation has established many of the general principles supporting our understanding of human molecular genetics.4 Furthermore, research into globin genes has greatly contributed to the understanding of how human gene expression is activated and silenced during differentiation and development.5, 6, 7, 8 Despite these advances, manipulation of globin gene expression to ameliorate or potentially cure the common disorders of these genes is not yet possible. Every 2 years since 1978, leading research groups have met at the Hemaglobin Switching Conference to report and discuss progress. In this Seminar we will summarise the understanding of the molecular and cellular pathophysiology, epidemiology, and management of β-thalassaemia, which is the main clinical problem in this specialty.1 We also review the developments reported at the 17th Hemaglobin Switching Conference in Oxford, UK, which offer renewed hope for novel approaches to treat these disorders.

Section snippets

Production of red blood cells

To fully understand the pathophysiology and management of thalassaemia, how red blood cells are normally produced (erythropoiesis), and how the globin genes are normally expressed at each stage of development should be considered. First, a transient cohort of embryonic red blood cells originate in the blood islands of the yolk sac. Definitive haemapoietic stem cells (HSCs), which persist throughout fetal and adult life, then emerge from the ventral wall of the dorsal aorta. These cells migrate

Normal expression of globin genes

Changes in the sites of erythropoiesis are associated with changes in the types of haemoglobin produced. At the molecular level, haemoglobin synthesis is controlled by two multigene clusters on chromosome 16 (encoding the α-like globins) and on chromosome 11 (encoding the β-like globins). In the human clusters, the genes are arranged along the chromosome in the order by which they are expressed during development to produce different haemaglobin tetramers: embryonic (Hb Gower-I [ζ2ɛ2], Hb

Variants that alter expression of globin genes

More than 200 β-thalassaemia alleles have been described in the database of human haemaglobin variants and thalassaemias, which involve mutations in any of the stages from transcription to RNA processing and translation of β-globin mRNA (figure 3).23 These mutations are detectable by DNA analysis and provide the basis for genetic counselling.24 Although most β-thalassaemias are caused by point mutations in the gene or its immediate flanking region, small deletions removing the β gene can also

The molecular and cellular pathology of β-thalassaemia

At each stage of development, the production of α-like and β-like globins is balanced. β-globin synthesis is normally controlled by the two β genes (one on each copy of chromosome 11). A mutation affecting one gene (β/βT or β-thalassaemia trait) usually causes no clinically significant problem, whereas patients who inherit deleterious mutations in both β genes (βTT) frequently have severe anaemia. The main pathophysiology in β-thalassaemia results from the synthesis of insufficient β chains

Epidemiology

WHO has estimated that about 1·5% of the world's population might be carriers of β-thalassaemia (β/βT) and that about 60 000 severely affected infants are born every year.44 These individuals mostly originate from the Mediterranean, Middle East, central Asia, India, and southern China, which suggests that there could be a selective advantage to carrying such a mutation in these areas. Similar observations have been made for α thalassaemia,1 which is even more widely distributed and more

Clinical phenotypes and standard management

The three broad clinical phenotypes in patients with β thalassaemia are major, intermedia, and minor. These phenotypes are associated with more than 200 different mutations that either reduce (β+-thalassaemia) or abolish (β0-thalassaemia) expression of the affected β-globin genes. Thalassaemia major occurs in homozygotes (βTT) or compound heterozygotes (eg, βTE) for such mutations. Affected individuals usually present with pallor, hepatosplenomegaly, and failure to thrive in the first year

Genetic testing and prenatal diagnosis

Initial screening of populations and identification of families at risk of producing infants who are affected by β thalassaemia has been achieved by examination of red-blood-cell indices and analysis of haemaglobin. The techniques to identify specific mutations underlying β thalassaemia in DNA from adults and fetuses are now well established and extensively applied to genetic counselling and prenatal diagnosis.24 New non-invasive techniques to analyse fetal DNA in the maternal circulation are

Pharmacological agents used to treat thalassaemia

The aims of therapeutic interventions for β thalassaemia are to increase expression of γ globin or to decrease expression of α globin, thus restoring the balance between α-like and β-like globin chains. Much evidence from clinical genetic studies shows that either (or preferably both) of these manipulations would have substantial clinical belenfits in patients with β thalassaemia.7, 12, 43, 63 Pharmacological studies have all focused on increasing expression of γ globin, but have been based on

Stem-cell transplantation for thalassaemia

In the past 30 years, stem-cell transplantation has substantially advanced treatment of thalassaemia major.67 Children who are identified before developing viral hepatitis or severe iron overload and who receive HLA-identical related donor stem-cell transplants have a very high likelihood of remission, with less than 10% mortality and minimal morbidity, apart from impaired fertility.67 Most groups report event-free survival of 80–90% for β thalassaemia.67, 69, 70, 71, 72 By contrast, event-free

Gene therapy for β thalassaemia

Thalassaemia was among the first genetic diseases for which gene therapy was proposed.82 This disorder is to some extent a good target because defects in expression of globin genes affect only the haemopoietic system and specifically affect erythropoiesis. Stem-cell transplantation is well developed for the haemapoietic system; however, unlike many genetic diseases, very high levels of tissue-specific gene expression are necessary to correct the globin defect in β thalassaemia. In principle,

Beyond gene therapy

In 2007, a landmark report96 described how human somatic cells (eg, skin fibroblasts) could be reprogrammed to form multipotent cells resembling embryonic stem cells. These reprogrammed cells are called induced pluripotent stem (iPS) cells.96, 97 Generation of iPS cells involves the introduction and expression of four transcription factors (Oct4, Sox2, KLF4, and c-Myc) in somatic cells. These transcription factors are normally needed to establish and maintain pluripotency. iPS cells have

Conclusions

Despite intensive clinical and scientific investigation of thalassaemia—a molecular disease that is perhaps better understood than any other—attempts to improve its management and to develop targeted drug therapy have not yielded a clear breakthrough. Stem-cell transplantation is an effective cure but still has a substantial risk of mortality and morbidity. Supportive results from cord-blood transplantation should encourage the development of cord-blood banking to address this issue. Gene

Search strategy and selection criteria

We searched PubMed using the terms “thalassaemia” in combination with “molecular basis” or “treatment” or “pathophysiology”. We mostly selected publications from from June 2006, to June 2011, but did not exclude frequently referenced and highly regarded older publications. We also searched the reference lists of articles identified by this search strategy and selected the most relevant ones. Review articles and book chapters are cited to provide readers with more details and more references

References (99)

  • NF Olivieri

    Thalassaemia: clinical management

    Baillieres Clin Haematol

    (1998)
  • MD Cappellini et al.

    A phase 3 study of deferasirox (ICL670), a once-daily oral iron chelator, in patients with beta-thalassemia

    Blood

    (2006)
  • DJ Pennell et al.

    Efficacy of deferasirox in reducing and preventing cardiac iron overload in beta-thalassemia

    Blood

    (2010)
  • L Krishnamurti et al.

    Hematopoietic cell transplantation for hemoglobinopathies

    Curr Probl Pediatr Adolesc Health Care

    (2008)
  • FJ Smiers et al.

    Hematopoietic stem cell transplantation for hemoglobinopathies: current practice and emerging trends

    Pediatr Clin North Am

    (2010)
  • G La Nasa et al.

    Unrelated donor bone marrow transplantation for thalassemia: the effect of extended haplotypes

    Blood

    (2002)
  • G Lucarelli et al.

    Advances in the allogeneic transplantation for thalassemia

    Blood Rev

    (2008)
  • A Boncimino et al.

    Cord blood transplantation in patients with hemoglobinopathies

    Transfus Apher Sci

    (2010)
  • TH Jaing et al.

    Rapid and complete donor chimerism after unrelated mismatched cord blood transplantation in 5 children with β-thalassemia major

    Biol Blood Marrow Transplant

    (2005)
  • DB Kohn

    Update on gene therapy for immunodeficiencies

    Clin Immunol

    (2010)
  • DA Persons et al.

    The degree of phenotypic correction of murine β-thalassemia intermedia following lentiviral-mediated transfer of a human γ-globin gene is influenced by chromosomal position effects and vector copy number

    Blood

    (2003)
  • C May et al.

    Successful treatment of murine β-thalassemia intermedia by transfer of the human β-globin gene

    Blood

    (2002)
  • S Rivella et al.

    A novel murine model of Cooley anemia and its rescue by lentiviral-mediated human β-globin gene transfer

    Blood

    (2003)
  • K Takahashi et al.

    Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors

    Cell

    (2006)
  • CL Harteveld et al.

    α-thalassaemia

    Orphanet J Rare Dis

    (2010)
  • R Galanello et al.

    Beta-thalassemia

    Orphanet J Rare Dis

    (2010)
  • DJ Weatherall

    Towards molecular medicine; reminiscences of the haemoglobin field, 1960–2000

    Br J Haematol

    (2001)
  • G Stamatoyannopoulos et al.

    Hemoglobin switching

  • DR Higgs et al.

    Long-range regulation of alpha globin gene expression during erythropoiesis

    Curr Opin Hematol

    (2008)
  • E Dzierzak

    A developmental approach to hematopoiesis

  • J Palis

    Ontogeny of erythropoiesis

    Curr Opin Hematol

    (2008)
  • S Philipsen et al.

    Erythropoiesis

  • DJ Weatherall et al.

    The thalassaemia syndromes

    (2001)
  • A Goren et al.

    Fine tuning of globin gene expression by DNA methylation

    PLoS One

    (2006)
  • J Miles et al.

    Intergenic transcription, cell-cycle and the developmentally regulated epigenetic profile of the human beta-globin locus

    PLoS One

    (2007)
  • BD Strahl et al.

    The language of covalent histone modifications

    Nature

    (2000)
  • AB Cantor et al.

    Transcriptional regulation of erythropoiesis: an affair involving multiple partners

    Oncogene

    (2002)
  • VG Sankaran et al.

    Advances in the understanding of haemoglobin switching

    Br J Haematol

    (2010)
  • M Gaszner et al.

    Insulators: exploiting transcriptional and epigenetic mechanisms

    Nat Rev Genet

    (2006)
  • B Giardine et al.

    Systematic documentation and analysis of human genetic variation in hemaglobinopathies using the microattribution approach

    Nat Genet

    (2011)
  • DC Rees et al.

    The hemoglobin E syndromes

    Ann N Y Acad Sci

    (1998)
  • MC Driscoll et al.

    γδβ-thalassemia due to a de novo mutation deleting the 5′ β-globin gene activation-region hypersensitive sites

    Proc Natl Acad Sci USA

    (1989)
  • D Kioussis et al.

    β-globin gene inactivation by DNA translocation in γ β-thalassaemia

    Nature

    (1983)
  • BG Forget

    Molecular basis of hereditary persistence of fetal hemoglobin

    Ann N Y Acad Sci

    (1998)
  • SL Thein et al.

    The molecular basis of β thalassemia, δβ thalassemia and hereditary persistence of fetal hemoglobin

  • J Borg et al.

    Haploinsufficiency for the erythroid transcription factor KLF1 causes hereditary persistence of fetal hemoglobin

    Nat Genet

    (2010)
  • AB Cantor

    GATA transcription factors in hematologic disease

    Int J Hematol

    (2005)
  • D Zhou et al.

    KLF1 regulates BCL11A expression and γ- to β-globin gene switching

    Nat Genet

    (2010)
  • G Galarneau et al.

    Fine-mapping at three loci known to affect fetal hemoglobin levels explains additional genetic variation

    Nat Genet

    (2010)
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